Association between post-transplant serum uric acid levels and ... - Plos

RESEARCH ARTICLE

Association between post-transplant serum uric acid levels and kidney transplantation outcomes Deok Gie Kim1☯, Hoon Young Choi2☯, Ha Yan Kim3, Eun Ju Lee3, Kyu Ha Huh1,4,5, Myoung Soo Kim1,4,5, Chung Mo Nam6, Beom Seok Kim2,5*, Yu Seun Kim ID1,4,5* 1 Department of Transplantation Surgery, Severance Hospital, Yonsei University Health System, Seoul, South Korea, 2 Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea, 3 Biostatistics Collaboration Unit, Yonsei University College of Medicine, Seoul, South Korea, 4 Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea, 5 The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, South Korea, 6 Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, South Korea

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☯ These authors contributed equally to this work. * [email protected] (YSK); [email protected] (BSK)

Abstract Background

OPEN ACCESS Citation: Kim DG, Choi HY, Kim HY, Lee EJ, Huh KH, Kim MS, et al. (2018) Association between post-transplant serum uric acid levels and kidney transplantation outcomes. PLoS ONE 13(12): e0209156. https://doi.org/10.1371/journal. pone.0209156 Editor: Kourosh Saeb Parsy, University of Cambridge, UNITED KINGDOM

Serum uric acid (UA) level has been reported to be associated with chronic allograft nephropathy and graft failure in patients who undergo kidney transplantation (KT). However, the role of serum UA level in renal graft survival remains controversial.

Objective This study aimed to investigate the effect of mean serum UA level during two different postKT periods on long-term renal graft outcomes in a large population cohort in which living donor KT prevails.

Received: June 11, 2018 Accepted: December 2, 2018 Published: December 14, 2018 Copyright: © 2018 Kim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: The authors received no specific funding for this work. Competing interests: The authors have declared that no competing interests exist.

Material and methods A retrospective cohort study was performed using KT data prospectively collected at a single institution. Patients (n = 2,993) were divided into low-, normal-, and high-UA groups according to the mean serum UA level within the first year (1-YR) and 1–5 years (5-YR) after transplantation.

Results In the 1-YR Cox proportional hazards analysis, the low- and high-UA groups had a significantly decreased and increased risk, respectively, for overall graft failure (OGF), death-censored graft failure (DCGF), and composite event (return to dialysis, retransplantation, death from graft dysfunction, and 40% decline in estimated glomerular filtration rate) compared with the normal-UA group. Similarly, in the 5-YR analysis, the low-UA group had a significantly reduced risk of DCGF compared with the normal-UA group, whereas the high-UA group had a significantly increased risk of all three graft outcomes. In a marginal structural

PLOS ONE | https://doi.org/10.1371/journal.pone.0209156 December 14, 2018

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Uric acid and long-term kidney transplantation outcomes

model, hyperuricemia had a significant causal effect on worsening graft outcomes, with consideration of all confounding variables (OGF: hazard ratio [HR] 2.27, 95% confidence interval [CI] 1.33–3.78; DCGF: HR 2.38, 95% CI 1.09–4.9; composite event: HR 3.05, 95% CI 1.64–5.49).

Conclusions A low-to-normal serum UA level within the first year and 1–5 years after KT is an independent factor for better renal allograft outcomes in the long-term follow-up period rather than high serum UA level.

Introduction Kidney transplantation (KT) has been considered the best treatment for patients with endstage renal disease. However, the exact mechanisms of renal graft failure remain unclear in pediatric and adult patients despite various studies on improvement in graft survival [1,2]. Therefore, many researchers have performed investigations to identify pathological mechanisms and risk factors for renal graft failure [3]. The mean serum uric acid (UA) level during the first 6 months after transplantation has been reported to be an independent predictor of long-term graft survival and short-term graft function [4], and early-onset hyperuricemia at 3 months after KT showed an increased risk for graft failure in the propensity-score matching analysis of a multicenter cohort study [5]. In contrast, previous randomized controlled trials have reported that serum UA level is not an independent risk factor for graft failure [5,6]. There was no association between renal function decline at 1 or 3 years and high UA levels at 1 month after KT after correcting for baseline renal function in a subanalysis of the Symphony study [6]. Furthermore, Kim et al. showed that serum UA level is not an independent risk factor for graft failure after accounting for graft function as a time-varying confounder [7]. However, numerous studies on patients with chronic kidney disease (CKD) have suggested a link between serum UA levels and renal dysfunction [8,9]. Moreover, treatment of asymptomatic hyperuricemia leads to improved patient and graft survival. Considering the link between UA level and risk of diabetes, metabolic syndrome, hypertension, and cardiovascular diseases, lowering the UA level to minimize these risk factors may be beneficial for graft function. Minimizing the use of diuretics and cyclosporine and avoiding purine-rich foods and alcohol are also effective strategies to decrease the serum UA level in KT recipients [10]. The present study aimed to investigate the effect of low, normal, or high post-transplant serum UA levels during two different post-KT periods on long-term renal graft outcomes in a large Korean population cohort in which living donor KT prevails. We used an approach that simultaneously accounts for time-varying exposures and confounders, allowing valid inferences to be made from complex longitudinal data in observational cohort studies [7,11].

Materials and methods Data source A retrospective cohort study was conducted using data of 2,993 patients who underwent KT from January 1992 to December 2014 at Severance Hospital, Yonsei University College of Medicine. The serum UA level was measured at 1, 3, 6, 9, and 12 months after transplantation


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and then annually throughout the study period. The serum creatinine level was also measured at the same time points, and the estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration formula [12].

Study population selection process The study population selection process and exclusion criteria are shown in Fig 1. Patients were divided into low-UA, normal-UA, and high-UA groups according to the mean serum UA level within the first year (1-YR) and 1–5 years (5-YR) after KT. High serum UA level was defined as a mean serum UA level >7.0 mg/dL in men and >6.0 mg/dL in women. Cutoff values for the low-UA group were defined using the sex-specific 10th percentile value from our data distribution (S1 Fig). Each group showed a similar serum UA level trajectory over time in the two analyses, maintaining the original grouping (S2 Fig). Patients with grafts and survival exceeding 1 year were included (n = 2,494) in the 1-YR analysis, with a mean follow-up period of 130.9±74.4 months (maximum, 302 months),

Fig 1. Algorithm used to define the study cohort. Uric acid (UA) grouping was performed according to the mean serum UA level within the first year (measured at 1, 3, 6, 9, and 12 months) and 1–5 years (measured annually) after transplantation in the 1-YR and 5-YR analyses, respectively. https://doi.org/10.1371/journal.pone.0209156.g001


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whereas patients who underwent KT from 2011 to 2014 and those with survival 40% decline in eGFR from the baseline level, which was measured at 1 year (1-YR analysis) or 5 years (5-YR analysis) after transplantation. The secondary endpoint was eGFR decline. The study was performed in accordance with the Declaration of Helsinki principles and approved by the independent institutional review board of Yonsei University College of Medicine (IRB no. 4-2017-0834). Moreover, the clinical and research activities being reported are consistent with the Principles of the Declaration of Istanbul as outlined in the “Declaration of Istanbul on Organ Trafficking and Transplant Tourism.”

Statistical analysis Group differences in baseline characteristics were evaluated using Pearson’s chi-squared test for categorical variables and one-way analysis of variance with post-hoc testing using Bonferroni’s method for continuous variables. The association between serum UA level and graft outcomes was evaluated using Kaplan–Meier survival curves and log-rank test (low- and high-UA groups versus normal-UA group). To determine whether UA group was an independent risk factor for the three graft outcomes, Cox proportional hazards analyses were performed with the following models: 1) model 1 adjusted for transplant era, age, sex, body mass index, donor type, donor age, donor sex, number of human leukocyte antigen mismatches, pre-transplant diabetes mellitus, duration of pre-transplant dialysis, retransplantation, tacrolimus use, delayed graft function, biopsy-proven acute rejection within 1 year, systolic/diastolic blood pressure, and eGFR at 1 month after KT and 2) model 2 adjusted for covariates in model 1 with eGFR at 1 year after KT rather than at 1 month. The results of the Cox analysis are presented as hazard ratios (HRs) with 95% confidence intervals. Repeated-measures variables, such as serum UA level and eGFR, were evaluated using a linear mixed model. We estimated eGFR variation based on the baseline value and evaluated group differences in eGFR changes over time. Considering serum UA level as a time-varying factor, time-varying Cox models were fitted with adjustment for baseline covariates to confirm the effects of serum UA level on graft outcomes. However, this analysis could not confirm a causal relationship between serum UA level and graft outcomes, as serum UA and eGFR affect each other. Therefore, we used marginal structural models (MSMs) [13] to estimate the causal effect of the time-varying serum UA level on graft outcomes in the presence of the time-varying confounder, eGFR, which is affected by the prior serum UA level. These models can be used to create a pseudo-population by implementing inverse probability of treatment weighting, which renders the relationship between serum UA level and other confounders, especially eGFR, independent. Because small errors could result in large weights, it was difficult to estimate the density of the serum UA level as a continuous or polytomous variable. Therefore, only two UA categories (high and normal) were used in the time-varying Cox models and MSMs. Multiple imputation using chained equations was used to handle missing data. Analyses were performed on five sets of imputed data, and estimates were combined using Rubin’s rules. Most statistical analyses were performed using SPSS version 23.0 (IBM Corp., Armonk, NY, USA). SAS version 9.4 (SAS Institute Inc., Cary, NC, USA) was used for the linear mixed model and time-varying Cox analyses, whereas R software version 3.4.3 (R Foundation for


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Statistical Computing, Vienna, Austria) was used for the MSMs and multiple imputation. Pvalues